Characterization of Neuronal Amino Acid Transporters: Uptake of Nitric Oxide Synthase Inhibitors and Implication for Their Biological Effects

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Abstract
In the present study we investigated uptake of the nitric oxide (NO) synthase inhibitors NG-methyl-l-arginine and NG-nitro-l-arginine by the mouse neuroblastoma × rat glioma hybrid cell line NG108-15. Uptake of NG-methyl-l-arginine was characterized by biphasic kinetics (Km1 = 8 µmol/L, Vmax1 = 0.09 nmol × mg−1× min−1; Km2 = 229 µmol/L, Vmax2 = 2.9 nmol × mg−1× min−1) and was inhibited by basic but not by neutral amino acids. Uptake of NG-nitro-l-arginine followed Michaelis-Menten kinetics (Km = 265 µmol/L, Vmax = 12.8 ± 0.86 nmol × mg−1× min−1) and was selectively inhibited by aromatic and branched chain amino acids. Further characterization of the transport systems revealed that uptake of NG-methyl-l-arginine is mediated by system y+, whereas systems L and T account for the transport of NG-nitro-l-arginine. In agreement with these data on uptake of the inhibitors, l-lysine and l-ornithine antagonized the inhibitory effects of NG-methyl-l-arginine on bradykinin-induced intracellular cyclic GMP accumulation, whereas l-tryptophan, l-phenylalanine, and l-leucine interfered with the effects of NG-nitro-l-arginine. These data suggest that rates of uptake are limiting for the biological effects of NO synthase inhibitors.

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